The molecular mechanisms that control unremitting lung fibrosis remain poorly understood, resulting in the unfortunate fact that targeted therapies for pulmonary fibrosis are lacking. This proposal focuses on elucidating the roles of ?rrestins (?r1 and ?r2) in regulating lung injury and fibrosis and to determining the feasibility that targeting ?rrestins as a novel therapeutic approach for lung fibrosis. Progressinve lung injury and fibrosis is a cause of major morbidity and mortality as in the case of idiopathic pulmonary fibrosis (IPF). We have demonstrated the roles of extracellular matrix (ECM), innate immune, and chemokine receptors in regulating lung injury and fibrosis. We recently identified that ?r1 and ?r2 play a role in fibrogenesis by regulating fibroblast invasiveness. ?rrestins are adaptor proteins for G-protein coupled receptors, some of which have been suggested to play a key role in lung fibrogenesis. One of the pathologic hallmarks of IPF is the destruction of basement membrane. In the bleomycin-induced mouse lung fibrosis model, loss of either ?r1 or ?r2 results in protection from mortality, inhibition of matrix deposition, and protected lung function. However, isolated lung fibroblasts from bleomycin-treated ?rrestin null mice fail to invade ECM while displaying altered expression of genes involved in matrix production and degradation. These data implicate ?rrestins as mediators of fibroblast invasion and development of pulmonary fibrosis, thus representing a potential target for therapeutic intervention for patients with IPF. Our data further showed that genes related to basement membrane degradation and cell-matrix adhesion were altered in ?rrestin deficient fibroblasts. Interestingly, ALL 13 these genes are regulated by transcription factor MyoD, 12 by oncogene Maf. Both MyoD and Maf have been shown to play a key role in cell differentiation by promoting cell cycle arrest. Our data suggest that MyoD and Maf interact with ?rs and regulate fibroblast invasion. Based on these data we have generated the hypothesis that (1) progressive lung fibrosis requires the the presence of ?rrestins and (2) ?rrestins complex with transcription factors MyoD and Maf leading to the development of a pathogenic fibroblast phenotype that invades tissue and transmits signals from the ECM to fibroblasts. We will test this hypothesis to determine the roles of ?rrestins of different cell types in regulating lung fibrosis; determine te role of MyoD-Maf in regulating ?r2-mediated fibroblast activation and fibrogenesis, as well as investigate the effect of the blockage of ?rrestin signaling on pulmonary fibrosis.